Process for preparing 17{60 -hydroxy-20-keto and 17{60 ,21-dihydroxy-20-keto pregnanes and derivatives and intermediates thereof

ABSTRACT

New processes for preparing 17 Alpha -hydroxy-20-keto and 17 Alpha ,21-dihydroxy-20-keto pregnanes and derivatives thereof, which compounds are useful as progestational and antiinflammatory agents. The processes utilize the steps of converting a 17 Alpha -ethynyl-17 Beta -acyloxy steroid to the corresponding 17-vinylidene steroid with zinc in an ethylene glycol ether and oxidizing the 17-vinylidene steroid to form the corresponding product pregnanes. The novel 17-vinylidene compounds are useful as intermediates as herein described and are also useful anti-androgenic agents.

United States Patent Crabbe et al.

[451 Aug. 1,1972

[72] Inventors: Pierre Crabbe; Esperanza Velarde,

both of Mexico City, Mexico [73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Aug. 7, 1970 [21] Appl. No.: 62,201

Related US Application Data [63] Continuation-impart of Ser. No.854,742, Sept.

2, 1969, abandoned.

[52] US. Cl. ..260/397.3, 195/51, 260/239, 260/55 C, 260/397, 260/397.4,260/397.45, 260/397.47, 260/397.5, 260/999 [51] Int. Cl ..C07c 169/10[58] Field of Search ..260/397.3, 397.4, 397.45, 397.47, 260/397.5,239.55 C

[56] References Cited UNITED STATES PATENTS 2,983,735 5/1961 Ruggieri..260/397.4 3,117,966 l/l964 Petrow ..260/239.55

Primary Examiner-Lewis Gotts Assistant Examiner-Ethel G. LoveAttorney-Evelyn K. Merker 5 7] ABSTRACT New processes for preparingl7a-hydroxy-20-keto and 17a,2l-dihydroxy-20-keto pregnanes andderivatives thereof, which compounds are useful as progestational andanti-inflammatory agents. The processes utilize the steps of convertinga l7a-ethynyl-1 7B-acyloxy steroid to the corresponding l7-vinylidenesteroid with zinc in an ethylene glycol ether and oxidizing the 17-vinylide'ne steroid to form the corresponding product pregnanes. Thenovel 17-vinylidene compounds are useful as intermediates as hereindescribed and are also useful anti-androgenic agents.

25 Claims, No Drawings This is a continuation-in-part of patentapplication,- Ser. No. 854,742, filed Sept. 2, 1969, now abandoned.

The present invention relates to a new process for the preparation oftherapeutically valuable steroid derivatives and to novel intermediatecompounds useful in this process. In particular, the present inventionis directed to a process for the preparation of 17ahydroxy-20-keto and17a ,2 l -dihydroxy-20-ketopregnane steroids and derivatives thereof vianovel, useful l7-vinylidene intermediates.

Steroid compounds which bear the 170; -hydroxy-20- keto and17a,2l-dihydroxy-20-keto system, the latter commonly referred to as thedihydroxy acetone side chain, demonstrate important and potentbiological activities. It is known that 17a -hydroxy-20-keto steroids,such as hydroxyprogesterone and various derivatives thereof, forexample, acetoxyprogesterone, chlormadinone acetate, and the like,possess progestational activity making them useful in fertility controland in the management of various menstrual disorders. It also has beendemonstrated that steroids having oxygen functions at positions G17,G20, and C-2l possess anti-inflammatory activity which make them usefulas agents for the treatment of arthritis, allergic dermatitis, contactdermatitis, and like conditions. Examples of compounds in this series ofsteroid which possess and have been used in accordance with suchactivity are beta-methasone, cortisone, dexamethasone, hydrocortisone,methylprednisolone, paramethasone, prednisolone, prednisone, andtriamcinolone. Many other steroids having the requisite l7a-hydroxy-20-keto or 1701 ,2l-dihydroxy-20-keto system which exhibit progestationaland/or corticoidal activity are known and have been describedrepeatedly, for example, in Steroid Drugs by Norman Applezweig; Vol. I,McGraw Hill Book Company, Inc., 1962, and Vol. 2, Holden Day, Inc.,1964.

Typical 17a -hydroxy-20-keto and 17a ,2l-dihydroxy-20-keto compoundswhich are prepared in accordance herewith are those of the followingpartial formula:

L-"ORI.

wherein, A is the remainder of the steroid molecule comprising the A, B,and C rings, R is hydrogen, hydroxy, or acyloxy, and R is hydrogen oracyl.

The present invention is directed to new processes and intermediatesuseful for the preparation of 17ahydroxy-20-keto and 17a,2l-dihydroxy-20-keto steroids of the pregnane series.

By employing, for the sake of convenience and simplicity, partialformulas of Ring D of the steroid molecule, the methods by which thesecompounds can be prepared in accordance herewith can be graphicallydepicted according to the following reaction sequence:

CHrR i=0 wherein Ac is lower acyl and each of R and R is as definedabove.

The present invention in a first, principal aspect resides in a processcomprising the step of treating a 17a -ethynyl-l7B-acyloxy-steroid ofthe estrane or androstane series l with zinc in an ethylene glycol etherto yield the corresponding l7-vinylidenesteroid (2).

The present invention is a second, principal aspect resides in a processcomprising the steps of treating a 17a -ethynyl-l7B-acyloxysteroid ofthe estrane or androstane series (1) with zinc in an ethylene glycolether to yield the corresponding l7-vinylidenesteroid (2) and oxidizingthe resulting l7-vinylidenesteroid (2).

The present invention in a third, principal aspect resides in novelcompounds depicted by partial Formula (2) above and defined morecompletely hereinafter. These compounds are useful as intermediates asherein described and as anti-androgenic agents useful for example in thetreatment of benign prostatic hypertrophy, hypersexuality in males,juvenile acne, and so forth.

In the foregoing process, the second (oxidation) step furnished the 17a-hydroxy-20-keto or 1701,21 dihydroxy-20-keto compounds or esterderivatives thereof (3). Thus, the usefulness of the first aspectresides in the process for preparing l7-vinylidene steroids which areuseful as (anti-androgenic agents and intermediates for the preparationof the 17a -hydroxy- 20-keto and l7 ,2l-dihydroxy-20-keto productshereof.

In accordance with the embodiments of the first aspect process of thepresent invention, a starting compound possessing in part the skeletonformula outlined by Formula (1) above is reacted together with zinc inan ethylene glycol ether. Suitable ethylene glycol ethers include themono and di lower alkyl ethers in the diethylene glycol and triethyleneglycol series such as diethylene glycol dimethyl ether, diethyleneglycol diethyl ether, diethylene glycol monoethyl monobutyl ether,diethylene glycol monomethyl ether, triethylene glycol monoethyl ether,triethylene glycol monomethyl monopropyl ether, triethylene glycolmonobutyl ether, triethylene glycol dimethyl ether, triethylene glycolmonopropyl ether, and the like. Preferred is diethylene glycol dimethylether (diglyme). This reaction is further conducted at a temperatureranging from about C. to about 220 C. and preferably at the boilingpoint of the reaction mixture and under reflux and for a period of timesufiicient to complete the reaction ranging from a few minutes toseveral hours, commonly from about 6 to about 8 hours.

The reaction is performed under anhydrous conditions, at least in theinitial stages of the reaction. Thus, in the preferred embodiments,anhydrous reaction conditions are followed for the entire reaction tocompletion or from the beginning and for a substantial periodsubstantially depending upon the total time of the reactlon.

The ethylene glycol ether is conveniently pre-treated with zinc prior tothe addition of starting steroid. Only as respect a preferredembodiment, this pre-treatment involves stirring or otherwise mixing theethylene glycol ether with zinc dust for a period of time ranging fromabout a few minutes up to several hours and preferably at about roomtemperature. It can then be filtered and subsequently used together withthe starting steroid and zinc in the principal reaction.

In accordance with the embodiments of the second aspect process of thepresent invention, the l7-vinylidene compound is prepared as describedabove and is then oxidized with oxidizing agent. Suitable oxidizingagents include osmium tetroxide, either alone or in combination withhydrogen peroxide; a percarboxylic acid, such as peracetic, perbenzoic,m-chloroperbenzoic, perphthalic, persuccinic, pertrifluoroacetic, andperformic, phenyliodoso acetate; and morpholine. These oxidizing agentsare known per se and their manners of use have been described in theliterature. See Fieser and Fieser, Steroids Reinhold Publishing Co.,

New York, 1959, page 659, and Hogg et al., Journal of the AmericanChemical Society 77, 4438 (1955), and Miescher, Helv. Chem. Acta 33,1840 (1950) and the references cited therein, all hereby incorporated byreference.

The oxidation reaction is conveniently performed in the presence ofinert, liquid organic reaction medium and at temperatures ranging fromabout 0 C. up to the boiling point of the reaction mixture. Suitablemedia include the tertiary alkanols such as tertiary butanol, tertiaryamyl alcohol and the like, and mixtures thereof; the hydrocarbonsolvents such as hexane, heptane, isoctane, decane, and the like, andmixtures thereof; the cycloalkyl hydrocarbon solvents, such ascyclopentane, cyclohexane, and the like, and mixtures thereof; themonocyclic aryl hydrocarbon solvents, such as benzene, toluene, cumene,xylene, and the like, and mixtures thereof; and the chlorinatedmethanes, such as methylene chloride, chloroform, and the like, andmixtures thereof. The choice of liquid reaction media is made takinginto consideration any potential interference or competition which maydevelop with the particular oxidizing agent employed, in accordance withthe level of ordinary skill of the art.

In the practice of the oxidation step, the choice of reactants, that is,oxidizing agent dictates whether a 1 7a -hydroxy-20-keto compound or a17a ,21-dihydroxy-20-keto compound or a derivative thereof will beprepared. When an oxidizing agent other than a peracid is employed, the1701 ,Zl-dihydroxy-ZO-keto corticoid compounds are formed. These can beacylated as a second step to the corresponding 17ahydroxy-Z l-acyloxy-20-keto products.

Conversely, in those instances wherein peracid is employed as oxidizingagent, a mixture of products is obtained. The compounds of this mixtureare products of peracid participation in the reaction, that is, acyloxymoieties derived from the acids used are introduced in the molecule soas to prepare the 1701 -acyloxy-20-keto pregnanes and17a-hydroxy-2l-acyloxy-ZO-keto compounds.

In carrying out the above described reaction steps, the respectivestarting compound and the respective reactant(s) are contacted andmaintained together in any convenient order or fashion, in accordancewith the preferences described. The reaction mixtures are thenmaintained within the given temperature range for a period of timesufi'icient to complete the reaction. Upon the completion of therespective reaction, the reaction mixture is processed by conventionalprocedures, such as dilution, filtration, extraction, decantation,distillation, evaporation, chromatography, and so forth to recover andisolate the desired product.

The given reactions consume the respective reactants in the ratio of onemole of the starting compound per mole of zinc and ethylene glycol etherand per two moles of oxidizing agent. However, the amounts of thereactants to be employed are not critical, some of the desired productbeing obtained when employing any proportions thereof. In the preferredembodiments hereof, the appropriate zinc and ethylene glycol etherreactants are employed in amounts ranging from about 25 to 50 moles upto about 500 moles per mole of the respective starting steroid compoundand the oxidizing agent in the amount ranging from about 2 moles toabout 10 moles per mole of the respective starting steroid compound.

The reaction can be conducted in the presence of catalytic amounts of astrong acid such as a mineral acid like hydrochloric acid, however, thisis not essential.

The process of the present invention is particularly useful for thepreparation of basic pregnane compounds which exhibit progestational andanti-inflammatory activity but, more importantly, which are also verysuitable as nuclei which can be further elaborated, in accordance withknown and standard methods, to prepare compounds exhibitingprogestational and anti-inflammatory activities considered valuablypotent in the steroid art. For example, the process hereof is notablysuited for the preparation of such basic compounds as hydrocortisone andcortisone or the l6-methyl or l6-hydroxy derivatives thereof.

The present process can be used with basic 17 -ethynyl-l7B-acyloxystarting compounds to prepare basic pregnanes which can be elaboratedfurther. Thus, the process can be practiced upon 3-keto-17 -ethyny1-l7l3-acyloxy-A compounds or upon 4,5-dihydro-3B- hydroxy (ethers orketals). In the latter instance, the C- 3 other groups can then becleaved, the 3hydroxyl oxidized to the ketone, and the A unsaturationintroduced according to the conventional procedures describedhereinafter. In either instance, the 3-keto-A compounds are furtherelaborated as respect the introduction of C-6 and C-9 and C-1 1 halogroups, A unsaturation, C-ll hydroxy, and so forth to prepare suchuseful compounds as flumethasone, prednisolone, prednisone, fluocinoloneacetonide, and the like.

The specific choice of starting material and the further elaboration iswithin the ordinary level of skill in the steroid art in accordance withthe present disclosure.

In the preferred embodiments hereof, the present invention is useful forthe preparation of 17 hydroxy-20 -keto and 17 ,2l-dihydroxy-20-ketocompounds having the following Formula (A):

R is hydrogen, fluoro, chloro or bromo, provided R is chloro when R ischloro; R is 0x0 or the group wherein R is hydrogen, hydroxy or chloro;

R is hydrogen or methyl;

R is oxo, ethylenedioxy, or the group CXY in which each of X and Y ishydrogen, chloro, or fluoro;

provided that when R is hydrogen, Z is a single bond.

The compounds represented by the above Formula (A) possessprogestational or anti-inflammatory activity and are thus useful as setforth above. Generally, those having a 113 and/or 2l-hydroxy group areantiinflammatory agents, the remainder being progestational compounds.In addition, however, the compounds of Formula (A) are also useful asintermediates for the preparation of other steroids which also possessvarying degrees of progestational or cortical activity making then alsouseful in fertility control and in the treatment of various inflammatoryconditions.

As indicated above, these compounds can be prepared directly from thecorresponding 17-oxo compounds or they are obtainable, in the preferredembodiments, upon further elaboration of a basic pregnane product.

The novel 17-vinylidene intermediate steroids of the present inventionare the l7-vinylidene compounds otherwise corresponding to the compoundsof Formula (A). A particularly valuable group of these compounds arethose represented by the following Formula (B):

wherein,

R is hydrogen, chloro, bromo, fluoro or methyl; R is hydrogen or methyl;R is oxo or the group hydrogen, hydroxy or a conventional hydrolyzableester or ether thereof;

each of Z and Z is a carbon-carbon single bond, a

carbon-carbon double bond, or the group each of X and Y is hydrogen,fluoro or chloro;

provided that when R is hydrogen, Z is a carbon-carbon single bond.

Preferably, the starting compounds possess the desired substitution inRing A and B, e.g., a keto or esterified B-hydroxyl group at C-3;chloro, bromo or a methyl group at C-6, methylene and halomethylenegroups at C-1,2 and/or C-6,7, or alternatively, groups which on furthertransformation give the desired substituent, such as 1,2 and/or6,7-oxido groups. Double bonds at 01 and/or C-6 may also be present inthe starting compounds or may be introduced after the main reaction byfollowing methods known to the skilled in the art.

The compounds depicted and defined above which can be prepared inaccordance with the processes hereof can be converted, via conventionalmeans known to one skilled in the art, to other useful deriva tives. TheC-l7 and C-2l hydroxyl groups, if present, can be conventionallyesterified, the primary alcohol requiring use of a carboxylic acidanhydride in the presence of, for example, pyridine and the 17a-tertiary alcohol requiring use of carboxylic acid anhydride in thepresence of acetic acid and p-toluenesulfonic acid. Similarly they canbe etherified to the conventional ethers in accordance also with methodsknown in the art other than direct methods upon oxidation (with chromicacid in pyridine) of a 3,8-hydroxy compound followed by treatment of the3-keto compounds with bromine in acetic acid in the presence of hydrogenbromide to yield the corresponding 2,4-dibromo-3-keto compound. Thisdibromo adduct is refluxed with sodium iodide in 2-pentanone to yieldthe corresponding 2- iodo-ii-keto-A compound which, when refluxed withcollidine, yields the corresponding 3-keto-A derivatlve.

If desired, the 3-keto compounds can be obtained by By refluxing the3-keto-A derivative with 2,3- dichloro-5,6-dicyano- 1,4-benzoquinone indioxane, the corresponding 3-keto-A" derivative is obtained. Byrefluxing the 3-keto-A derivative with chloranil and xylene, thecorresponding 3-keto-A' derivative is obtained.

The corresponding llfl-hydroxy derivative of the above depicted anddefined compounds can be prepared by incubating the G11 dihydrocompounds with any hydroxylating microorganism, such as CunninghamellaBainieri or Curvalaria Lunata, in an appropriate nutrient medium or byselective reduction of a 1 l-keto group.

The 3-keto-A compounds can be converted into the corresponding 6-fluoroderivatives by transformation into the 3-ethylenedioxy-A compoundsfollowed by treatment with hydrofluoric acid and N-bromoacetamide in thepresence of a proton acceptor, followed by dehydrobrornination andisomerization of the 6,6- fluoro to the -isomer by acid treatment, or byconversion of the 3-keto-A compounds into the 3-enol ethers or enolesters and reaction of the enol compounds with perchloryl fluoridefollowed by acid treatment. When the 3-enol ethers are reacted withN-chlorosuccinimide there are obtained the corresponding 6B-chloroA-3-keto compounds which are converted into the Qtisomers by acid treatment.The respective 6-brorno compounds are obtained by usingN-bromosuccinimide. 1n the preferred embodiments hereof, it is preferredto introduce a chloro or bromo substituent at C-6 after the introductionof the vinylidene group or at total process end.

The 3-keto-A compounds can also be converted into the corresponding3B-hydroxy compounds by reduction with a double metal hydride such aslithium tri( tertiarybutoxi)aluminu.m hydride, zinc borohydride and thelike, and the 3-hydroxy group esterified later with carboxylic acidanhydrides or carboxylic acid chlorides in pyridine solution, oretherified with dihydropyran, dihydrofuran, or 4-methoxy dihydropyran inthe presence of an acid catalyst.

Protection is preferably provided for those groups present in thestarting compound which may compete or interfere with the principalreactions hereof or with the processes preparative to the principalreactions hereof. The oxidation step hereof requires that any hydroxylgroups which are present on the starting material be protected by eitheresterifying them with a carboxylic acid anhydride such as aceticanhydride, propionic anhydride, caproic anhydride, and the like in atertiary amine solvent such as triethyl amine, pyridine, quinoline, andthe like or by etherification. A mild subsequent hydrolysis restores thehydroxyl group.

In accordance with the above, products which can be prepared inaccordance with the preferred. embodiments hereof and also in accordancewith the generic process of the present invention, the startingmaterials which are represented above by partial Formula 1, areoptionally substituted with alkyl, halogenated alkyl, hydroxy, acyloxy,halogeno, alkoxy, oxido, methylene, acetyl, ketal, cyano, and the like.For example, the starting materials can be substituted with2,3-isopropylidenedioxy, l-acetylthio, l-cyano, 1,2-oxido, 2-alkyl,2-formyl, 2-halo, 4hydroxy, 4-acetoxy, 4-halo, 5- hydroxy, S-acetoxy,4,5-oxido, 6-hydroxy, 6-acetoxy, 6-halogenated methyl, -fluoro,6-methyl, 5,6oxido, 9-

8 halo, ll-keto, ll-hydroxy, ll-halo, 9,1l-oxido l2-a1- kyl, lZ-hydroxy,l5-alkyl, IS-hydroxy, l6-alkanoyloxy, l6-alkyl, l6-halogenated methyl,15,16-oxido, l8-alkyl, l9-alkyl, l9-hydroxy, l9-carboxy and the like.

The starting compounds for the present invention are known or they canbe prepared by treating a l7-ketoandrostane with an ethynylating agentin accordance with known, conventional methods to prepare thecorresponding 1701 -ethynyl-l7B-ol compound and thereafterconventionally esterifying this derivative to the corresponding 17a-ethynyl-17B-acyloxy compound. The conventional ethynylation involvesthe use of an alkali metal acetylide or acetylene, alkali metal alkoxideand dimethyl sulfoxide-see US. Pat. Nos. 3,126,376 and 3,470,270 and theconventional esterification involves the use of carboxylic acidanhydride in benzene with acid catalyst.

Such compounds are described, inter alia, in U.S.

Pats. Nos. 2,843,609, 2,964,547, 2,946,809, 3,028,401, 3,047,592,3,062,844, 3 ,064,0 1 4, 3,080,391, 3,096,355, 3,102,897, 3,178,412,3,270,037, 3,338,928, 3,414,592, 3,444,295,

3,452,058 and 3,462,465. The 3B/3-diacyloxy-17aethynyl-A -startingcompounds can be obtained by reduction of the corresponding A -3-ketoandrostene or estrene derivatives with lithium tri(tertiarybutoxy)aluminum hydride or another double metal hydride followed byconventional esterification of the hydroxy groups at C-3and G17.

In the present specification and claims, the following definitionsapply.

The wavy line used in the depicted formulas indicates that thesubstituents attached to those positions can be either in theconfiguration alpha (or) or beta (B) or mixtures thereof.

The term conventional hydrolyzable ester denotes those hydrolyzableester groups conventionally employed in the steroid art, preferablythose derived from hydrocarbon carboxylic acids. The term hydrocarboncarboxylic acid defines both substituted and unsubstituted hydrocarboncarboxylic acids. These acids can be completely saturated or possessvarying degrees of unsaturation (including aromatic), can be of straightchain, branched chain, or cyclic structure, and preferably contain fromone to 12 carbon atoms. In addition, they can be substituted byfunctional groups, for example, hydroxy, alkoxy containing up to sixcarbon atoms, acyloxy containing up to twelve carbon atoms, nitro,amino, halogeno, and the like, attached to the hydrocarbon backbonechain. Typical conventional hydrolyzable esters thus included within thescope of the term and the instant invention are acetate, propionate,valerate, caproate, enanthate, caprylate, perlargonate, acrylate,undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate,diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate,methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate,adamantoate, glycolate, methoxyacetate, hemisuccinate, hetniadipate,herrri-B,B-dimethylglutarate, acetoxyacetate, 2-chloroacetate,B-chloropropionate, trichloroacetate,[3-chlorobutyrate,bicyclo-[2.2.2]-octane- 1 -carboxylate,4-methylbutylo-[ 2.2.2 l-oct-Z-enel-carboxylate and the like. Thepreferred conventional ester is acetate.

Conventional hydrolyzable ethers include the cyclopentyl,tetrahydrofuran-2-yl, tetrahydropyran-2'- yl, and4'-methoxy-tetrahydropyran-4'-yl ethers.

The term lower alkyl defines aliphatic hydrocarbons of from one to sixcarbon atoms including all isomers thereof. Typical lower alkyl groupsare methyl, ethyl, isopropyl, t-butyl, isoamyl and n-hexyl.

The term halogenated methyl defined a methyl group substituted with one,two or three halogen groups, preferably chloro and fluoro. Typicalhalogenated methyl groups include fluoromethyl, chloromethyl,difluoromethyl, chlorofluoromethyl, trichloromethyl, trifluoromethyl andthe like.

The terms acyl or acyloxy define acyl and acyloxy groups derived fromlower alkanoic acids containing from two to four carbon atoms, that is,acetic, propionic, and the butyric acids or those derived from theperacids within the scope hereof.

The following examples typify the manner by which the present inventioncan be practiced and represent, in one aspect, the best mode forcarrying out the invention. As such, they should be construed merely asillustrative and not as limitative upon the overall scope hereof.

PREPARATION l A solution of l g. of 3B-acetoxy-5a-andr0stan-17- one, in30 ml. of anhydrous benzene is added under nitrogen to a solution ofpotassium in 30 ml. of t-amyl alcohol previously saturated withacetylene. A slow current of purified acetylene is continually passedthrough the solution for 40 hours. The mixture is diluted with water andextracted with benzene. These extracts are washed with water toneutrality, dried over sodium sulfate and evaporated. Chromatography ofthe residue on alkaline alumina with 2:3 hexanezbenzene yields 3,B-acetoxy- 1 7 -ethynyl-5 -androstan- 1 78-01 which is recrystallizedfrom acetonezhexane.

To a solution of g. of 3B-acet0xy-l7a-ethynyl-5aandrostan-l7B-ol in 250ml. of anhydrous benzene are added 2 g. of p-toluenesulfonic acid and 10ml. of acetic anhydride, and the mixture is allowed to stand for 24hours at room temperature, poured into icewater and the resultingmixture stirred to effect hydrolysis of the excess anhydride. Thebenzene layer is separated and washed with 10 percent sodium carbonatesolution and water. Drying, evaporation and crystallization of theresidue from acetone-hexane affords 3B, 1 7B-diacetoxyl7a-ethynyl-5a-androstane.

In like manner, by following the esterification procedure in theimmediately foregoing paragraph, but substituting propionyl anhydride,butyryl anhydride, pentanoyl anhydride, caproyl anhydride, heptanoylanhydride, and capryloyl anhydride for acetic anhydride there areobtained the corresponding 17B-propionyloxy, -butyryloxy, pentanoyloxy,-caproyloxy, -heptanoyloxy, and -capryloxy esters in the 3B-acetoxy-l7a-ethynyl-Sa -androstane series.

In like manner, the foregoing processes can be used to prepare thefollowing representative compounds:

61 -methyl- 1 7a-ethynyl- 1 7B-acetoxyestr-4-en-3-one,

61 chloro- 1 7a-ethynyll 7B-acetoxyandrost-4-en-3- one,

61 -chloro-1 7a-ethynyll 7B-acetoxyestr-4en-3-one,

6a-fluorol 7a-ethynyll 7B-acetoxyandrost-4-en-3- one,

one,

Ga-fluoro- 1 7a-ethynyl-1 7B-acetoxyestr-4-en-3-one,

6a ,7a-difluoromethylene- 1 7a-ethynyl- 1 7B-acetoxyandrost-4-en-3-one,

6a,7a-methylenel 7a-ethynyll 7B-acetoxyandrost- 4-en- 3-one,

6a ,7a-difluoromethylene- 1 7a -ethynyl-l 7B-acetoxyester-4-en-3-one,

6a,7a-methylenel 7a-ethynyll 7B-acetoxyestr-4- en-3-one,

la,2a-difluoromethylenel 7a-ethynyll 7B-acetoxyandrost-4-en-3-one,

. la,2a-methylene-6a,7a-difluoromethylene- 1 7aethynyl- 17B-acetoxyestr-4-en-3-one,

6a -methyl- 1 7a-ethynyll 7B-acetoxyestr-4-ene,

6-methyll 7a-ethynyll 7B-acetoxyandrosta-4,6-

dien-3-one,

6-chloro- 1 7a -ethynyl- 1 7B acetoxyestra-4 ,6-dien-3- one,

6-fluoro- 1 7a -ethynyl- 1 7fl-acetoxyestra-4,6-dien-3- one,

l7a-ethynyl- 1 7B-acetoxyandrostal ,4,6-trien-3-one,

6a-chl0rol 7a-ethynyll 7,8-acetoxyandrostal ,4-

dien-3-0ne,

l 7a-ethynyll 7,8-acetoxyandrostal ,4-dien-3-one,

l 7a-ethynyll 7B-acetoxyandrost-4-ene,

The completely esterified derivatives of:

9a-fluor0-17a-ethynyll 7B-acetoxy-5a-androstane 3B, 1 1B-diol, l6a-methyl- 17a-ethynyl- 1 7,8-acetoxy-5a-androstan-3B-ol-l l-one,3,3-ethylenedioxy- 1 7a-ethynyl- 1 7,8-acetoxy-5a-androstan- 1 601-01,61 -methyl-9oz-fluoro- 1 7a -ethynyl 1 7B-acetoxy-5 a-androstane-3/3, lIB-diol, 6B, 1 6a-dimethyl-l 7aethynyl-l7,8-acetoxy-Sa-androstan-SB-ol,as well as the corresponding 17B-propionyloxy, -butrylox- Y y,-pentan0yloxy, -caproyl0xy, -heptanoyloxy, and

-capryloyloxy esters thereof.

PREPARATION 2 To a solution of 1 g. of l7a-ethynylandrost-4-en-17B-ol-3-one of 50 ml. of tetrahydrofuran is added 2 g. of lithiumtn'(tertiary butoxy)aluminum hydride, and the resulting mixture isstirred at room temperature for 1 hour, and then acidified with diluteaqueous acetic acid. The acidified aqueous mixture is extracted withchloroform and the organic extract washed successively with water,aqueous sodium bicarbonate and water to neutrality, dried over sodiumsulfate and evaporated to dryness. The residue is recrystallized fromethermethanol, to yield the pure 17a -ethynylandrost-4-ene- 3,8, l7,8-diol.

Upon esterification of the foregoing dihydroxy compound by the method ofthe preceding Preparation there is obtained3B,l7B-diacetoxy-17a-ethynylandrost-4-ene.

PREPARATION 3 of pyridine is added to a mixture of 0.6 g. of chromiumtrioxide in 2 ml. of pyridine. The reaction mixture is allowed to standat room temperature for 15 hours, diluted with ethyl acetate andfiltered through Celite, diatomaceous earth. The filtrate is washed wellwith water, dried and evaporated to dryness to yield 6,6- fluoro-fi ,7a-difluoromethyleneandrost-4ene-3, 1 7- dione.

Through a stirred suspension of l g. of sodium methoxide in 8 ml. ofdimethylsulfoxide at room temperature, there is passed a slow stream ofpurified acetylene over a period of 20 minutes. Then it is added asolution of 1 g. of fi-fiuoro-dx ,7-difluoromethyleneandrost-4-ene-3,l7-dione in 15 ml. of anhydroustetrahydrofuran. The introduction of acetylene is continued for threehours. At the end of this time, the reaction mixture is poured into 100ml. of water containing 0.2 ml. of concentrated sulfuric acid. Thetetrahydrofuran is evaporated and the solid which forms is collected byfiltration, washed with water to neutrality and air dried. This materialis clarified with charcoal and recrystallized from acetone to yield6B-fluoro-6a,7adifluoromethylene- 1 7a -ethynylandrost-4-en-l 7,8-01-3-one, which is converted into the l7fiacetate by following theesterification method of Preparation 1.

EXAMPLE 1 Anhydrous diethylene glycol dimethyl ether (2 lt.) is stirredwith 100 g. of zinc dust for a period of two hours. Following thisperiod, the resultant mixture is filtered and to the filtrate is added100 g. of l7fi-acetoxy- 17a -ethynylandrost-4-en-3-one. To the resultantmixture are then added 1,000 g. of zinc dust with stirring in aportion-wise fashion, in a one hour period. Following this addition, theresultant mixture is heated to the boiling point and maintained underreflux and anhydrous conditions for 7 9t hours. The reaction mixture isthen filtered, the solid is washed with 1 it. of hot chloroform and thecombined organic solutions evaporated to dryness under reduced pressure.The residue is chromatographed on alumina eluting with hexanezmethylenechloride (95:5) to obtain 17-vinylideneandrost-4-en-3- one.

in a similar manner, the l7fi-acetoxy-l7aethynylestr-4-en-3-one, l7,8-acetxy-6u -chloro-l7a ethynylandrost-ONE AND -&-propionoxy-&1, 7methylenestr-4-en-3-one are converted respectively intol7-vinylidenestr-4-en-3-one, fix-chlorod7-vinylideneandrost-4-en-3-oneand 6a 7a -methylene-l7- vinylidenestr-4-em3-one.

EXAMPLE 2 One hundred milliliters of diethylene glycol dimethyl ether isdistilled. The distillate is refluxed over sodium metal for a period of2 hours, after which time it is removed by distillation. Fifteenmilliliters of the thus prepared anhydrous diethylene glycol dimethylether is stirred together with zinc dust for a period of 2 hours at roomtemperature. After this time, the mixture is filtered and to thefiltrate is added 1 g. of 33, 17B- diacetoxy-17q-ethynylestra-4,6-diene, at room temperature. To the resultant solutionare added. 10 g. of zinc dust in a portionwise fashion at roomtemperature. Following the addition, the reaction mixture is heated tothe boiling point and maintained under reflux conditions for 7 hours.During this entire period. the anhydrous conditions are maintained.Following the reflux period, the solution is filtered, concentratedunder high vacuum, and the residue chromatographed over Florisil elutingwith hexane-ether (:5) to provide the3B-acetoxy-l7-vinyl-idenestra-4,6-diene product.

By the same method 3B, l7/3-diacetoxy- 1 7a -ethynylandrosta-4,6-diene,33,17/3-diacetoxy- 1 7a ethynylestr-4-ene and 3B,l7fldiacetoxy-61-methyl-l7 a -ethynylandrost-4-ene are convertedrespectively into 3B-acetoxy-l7-vinylidene androsta-4,6-diene, 3B-acetoxy-l7-vinylidenestr-4-ene and SB-acetoxy-tnmethyl-17-vinylideneandrost-4-ene.

EXAMPLE 3 One gram of 61-methyl-l7B-propionoxy-l7a-ethynyl-estr-4-ene isadded to 50 ml. of anhydrous diglyme (prepared as described in Example2, above) at room temperature with stirring. To the resultant solutionare added 15 g. of zinc dust while maintaining the mixture at roomtemperature and under stirring. After the ad dition of the zinc dust, 5drops of 36 percent hydrogen chloride are added to the resultantmixture. The reaction mixture is then heated to the boiling point andmaintained under reflux and anhydrous conditions for 15 hours. Themixture is then filtered, concentrated and the resultant residuechromatographed over fiorisil eluting with hexane-ether (95:5) to aifordfizz-methyll 7-vinylidenestr-4-ene.

EXAMPLE 4 A portion of anhydrous triethylene glycol dimethyl ether isprepared in accordance with the procedure set forth in Example 2, fordiethylene glycol dimethyl ether. The resulting anhydrous triethyleneglycol dimethyl ether is then treated with zinc dust at refluxtemperatures as described for diethylene glycol dimethyl ether inExample I. To the resulting zinc treated, anhydrous triethylene glycoldimethyl ether is added 1 g. of la .70: -d.ifluoromethylene-l7B-acetoxyl 7 a-ethynylandrost-4-en-3-one. To the resulting solution isthen added, at room temperature and with stirring, 25 g. of zinc dust ina portion-wise fashion. Following this addition, the reaction mixture israised to the boiling point and maintained under reflux and anhydrousconditions for a period of 6 hours. The reaction mixture is thenfiltered, concentrated, and the residue chromatographed on florisil thusyielding 61,2adifluoromethylenel 7-vinylideneandrost-4-en-3-one.

EXAIVIPLE 5 Fifty milliliters of diethylene glycol monoethyl ether ismade anhydrous and pretreated with zinc dust in accordance with themethods set forth in Examples 1 to 4, above. To this anhydrous,pretreated diethylene glycol monoethyl ether are added 2 g. of6,8-tluoro-6u,7adifluoromethylene- 1 7a -ethynyl- 17B-acetoxyandrost-4-en-3-one. To the resulting solution are added 50 g. of zinc dust in aportion-wise fashion and at room temperature while stirring. Followingthe addition of the zinc dust, 1 ml. of 36 percent hydrogen chloridesolution is added to the reaction mixture. The reaction mixmatographedture is then heated at the boiling point for a period of three hourswhile maintaining the entire mixture under anhydrous conditions.Following the reflux period, the solution is filtered, concentrated, andthe residue chroto yield 6B-fluoro-61 ,7q difluoromethylenel7-vinylideneandrost-4-en-3-one;

EXAMPLE 6 One hundred milliliters of anhydrous diethylene glycoldirnethyl ether which has been pretreated with zinc is prepared asdescribed in the foregoing examples. To this is added one gram of1a,2a-methylene-l7B- acetoxy-l7 -ethynylestr-4-en-3-one. To theresultant solution are added 10 g. of zinc dust in a portion-wisefashion with stirring and at room temperature. Following the addition ofthe zinc dust, the reaction mixture is heated to the boiling point andmaintained under reflux conditions for a period of hours. During thefirst 8 hours of the reflux period, measures are taken to maintain thereaction mixture anhydrous. Following the reflux period, the solution isfiltered and the filtrate is evaporated to dryness under reducedpressure. Chromatography of the residue on washed alumina yields 141 ,2a-methylenel 7-vinylidenestr-4-en-3-one.

EXAMPLE 7 Part A- 3B-Acetoxy-l7-vinylidene-5a -androstane Anhydrousdiethylene glycol dirnethyl ether (40 ml.) is stirred with zinc dust fora period of 2 hours. Following this period, the resultant mixture isfiltered and to the filtrate is added 1 g. of3B,l7B-diacetoxy-17a-ethynyl-Sa -androstane. To the resultant mixtureare then added 12 g. of zinc dust with stirring in a portion-wisefashion. Following this addition, the resultant mixture is heated to theboiling point and maintained under reflux and anhydrous conditions for 7A hours. The reaction mixture is then filtered and concentrated undervacuum to obtain a residue. The residue is chromatographed on florisileluting with hexane:ether (95:5) to obtain the3B-acetoxy-l7-vinylidene-5a-androstane product.

Part B-l 3B-Acetoxy-5a -pregnane-l7a,21-diol- -0ne A solution of 200 mg.of 3B-acetoxy-l7-vinylidene- 5a -androstane dispersed in 0.5 ml. ofpyridine is added to a mixture of 3 ml. of benzene containing 350 mg. ofosmium tetroxide. After the addition, the resultant mixture is allowedto stand at 20 C. for 15 hours. After this time, a solution of 50 ml. ofwater containing 3 g. of sodium sulfite and 3 g. of potassiumbicarbonate is added. The benzene is then quenched on a vacuum and a fewmilliliters of ethanol are poured into the mixture. The resultantmixture is then stirred at 20 C. for 12 hours. Following this period, afew drops of acetic acid are added until the mixture is neutral. Thereaction mixture is then evaporated and extracted with chloroform toprovide the 3B-acetoxy-5a-pregnane- 17a ,2l-diol-20-one product whichcan be further purified by chromatography on florisil. Part B-23B-Acetoxy-5a -pregnanel7a,21-diol-20- one To a solution of 200 mg. of3B-acetoxy-l7-vinylidene-Swandrostane dispersed in 80 ml. of diethylether, there is added 1 g. of osmium tetroxide in three drops of water.The reaction is allowed to stand at tion and water, dried over sodiumsulfate, and

evaporated. The residue purified on chromatographic magnesium silicateeluting with hexane, and then with hexane:ethyl acetate (4: 1) to yieldthe 3fi-acetoxy-fizpregnane- 1 7a ,21-diol-20-one product. Part B-33B-Acetoxy-17a -(3-chlorobenzoyloxy)- Swpregnan-ZO-one and3B-acetoxy-2l-(3- chlorobenzoyloxy )-5a -pregnan- 1 7a -ol-20-one To asolution of l g. of 3,8-acetoxyl 7-vinylidene-5a androstane dispersed in20 ml. of chloroform are added 1.3 g. of 85 percent m-chloroperbenzoicacid. The resultant reaction mixture is allowed to stand at roomtemperature for 24 hours. After this period it is washed with sodiumbicarbonate, dried over sodium sulfate, and evaporated. The residueafter evaporation is chromatographed on florisil eluting with benzene:2percent ethyl acetate to provide the 3,8-acetoxy-l7 3'-chlorobenzoyloxyyix -pregnan-20-one and the 3/3- acetoxy-2 l-( 3'-chlorobenzoyloxy)-5a -pregnan-1 7a -ol- 20 -one product.

EXAMPLE 8 Part A 9h -Fluorol 7-vinylidene-5a -androstane- 33,1 1 B-diolOne hundred milliliters of diethylene glycol dirnethyl ether isdistilled. The distillate is refluxed over sodium metal for a period of2 hours, after which time it is removed by distillation. Fifteenmilliliters of the thus prepared anhydrous diethylene glycol dirnethylether is stirred together with zinc dust for a period of 2 hours at roomtemperature. After this time, the mixture is filtered and to thefiltrate is added 1 g. of Q1 -fluoro-l 7a ethynyl-17B-acetoxy-5aandrostane-33,1 l ,B-diol at room temperature. To the resultant solutionare added 10 g. of zinc dust in a portion-wise fashion at roomtemperature. Following the addition, the reaction mixture is heated tothe boiling point and maintained under reflux condition for 7 hours.During this entire period, the anhydrous conditions are maintained.Following the reflux period, the solution is filtered, concentratedunder high vacuum, and the residue chromatographed over florisil elutingwith hexane:ether (:5) to provide the 9x -fluorol7-vinylidene-5a-androstane-3B, 1 1B- diol product.

Conventional acetylation with acetic anhydride in pyridine at roomtemperature provides 3B-acetoxy-9a fluoro- 1 7-vinylidene-5a -androstanl1 13-01.

Part B-l 9a-Fluoro-5a-pregnane-3B,11B,l7a,21- tetraol-20-one A mixtureof g. of 9 -fluoro-l7-vinylidene-5aandrostane-3,8,1 l B-diol and 1.5 l.of diisopropyl ether is added to a mixture of 102 g. of osmiumtetroxide, 500 ml. of diisopropyl ether and 5 ml. of water. Theresulting mixture is stirred for 4 days at 40 C. cooled and filtered.The filtrate is washed with aqueous sodium thiosulfate solution andwater, dried over magnesium sulfate and evaporated. The residue ischromatographedon magnesium silicate eluting with isooctane to yield the9a-fluOrO-5a -pregnane-3B,l 1B,l7a,21- tetraol-20-one product.

Part B-2 3B,l7a-Diacetoxy-9a-fluoro-5orpregnanl1B-ol-20-one3,8,2l-Diacetoxy-9a-fluoro-5apregnane-l 1B, 1 7a -diol-ol-20-one To amixture of 60 g. of sodium carbonate which is dispersed in ISO ml. ofmethylene chloride, are added 30 ml. of 13 percent peracetic acid withstirring and at room temperature. The mixture is allowed to stand atroom temperature for 75 minutes after which time it is filtered. Sodiumsulfate is added to the filtrate and this mixture is again filtered. Tothe filtrate are added three grams of sodium carbonate and one gram ofBB-acetoxy-Eh -fluoro-17-vinylidene-5u -androstan-l 1 8-01. Theresultant mixture is stirred at room temperature for 24 hours afterwhich time it is subjected to a vacuum. After removing the vacuum, ethylacetate is added to the mixture and the resulting mixture is extractedwith sodium bicarbonate, water and a saturated solution of sodiumchloride. The resulting solution is evaporated to a residuewhich ischromatographed on Florisil eluding with benzene: 2 percent ethylacetate to provide the 3,8,1 7a -diacetoxy-9 -flu'oro-5 -pregnan-llB-ol-20- dione and 3B ,21-diacetoxy-Q dluoro-S -pregnane- 1 1B, 1 7a-diol-20-one products.

EXAMPLE 9 Part A lfi -Methyll7-vinylidene-5a -androstan-3flol-l l-oneOne gram of 16, -methyl-l7a -ethynyl-l7B- propionyloxy-Sa-androstan-3fi-ol-l l-one is added to 50 ml. of anhydrous diglyme(prepared as described in Example 2, above) at room temperature withstirring. To the resultant solution are added 15 g. of zinc dust whilemaintaining the mixture at room temperature and under stirring. Afterthe addition of the zinc dust, drops of 36 percent hydrogen chloride areadded to the resultant mixture. The reaction mixture is then heated tothe boiling point and maintained under reflux and anhydrous conditionsfor 15 hours. The mixture is then filtered, concentrated and theresultant residue chromatographed over florisil eluting withhexane2ether (95:5) to provide the 1&1-methyl-l7-vinylidene-5a-androstan-3B-ol-l l-one product. Part A-23,8-Acetoxy-l61-methyl-l7-vinylidene-5aandrostan- 1 1 -one A mixture of204 g. of 16 -methyl- 1 7-vinylidene-Sa androstan-BB-ol-l l-one, 600 ml.of pyridine and 300 ml. of acetic anhydride is allowed to stand at roomtemperature for 24 hours. The mixture is then poured into ice-water andthe solid which forms is collected by filtration, washed with water anddried to yield 313- acetoxyl 61 -methyl- 1 7-vinylidene-5 -androstanl 1-one which is further purified through recrystallization fromacetonezhexane. Part B 3,8-Acetoxy-l6 -methyl-5a pregnanc- 17a,21-diol-1 1,20-dione A mixture of 166 g. of 3,8-acetoxy-l6 -methyl-l7-vinylidene-S androstan-l l-one in 1.5 l. of tetrahydrofuran is added toa mixture of 456 g. of osmium tetroxide, 500 m1. of tetrahydrofuran and5 ml. of water. The resulting mixture is stirred for 20 days at 30 c.,cooled and filtered. The filtrate is washed with aqueous sodiumthiosulfate solution and water, dried over sodium sulfate andevaporated. The residue is chromatographed on chromatographic magnesiumsilicate eluting with cyclohexane to yield 3,8-acetoxy- 161- rnethyl-Sa-pregnane- 1 7 ,2 l-diol-l l ,ZO-dione.

EXAMPLE 10 Part A 3,3-Ethylenedioxy-l7-vinylidene-Sa -androstan-lQx-ol Aportion of anhydrous triethylene glycol dimethyl ether is prepared inaccordance with the procedure set forth in Example 2, for diethyleneglycol dimethyl ether. The resulting anhydrous triethylene glycoldimethyl ether is then treated with zinc dust at reflux temperatures asdescribed for diethylene glycol dimethyl ether in Example 1. To theresulting zinc treated, anhydrous triethylene glycol dimethyl ethersolution is added 1 g. of3,3-ethylenedioxy-l7a-ethynyl-l7B-butyroyloxy-51-androstan-ldz-ol. Tothe resulting solution is then added, at room temperature and withstirring, 25 g. of zinc dust in a portion-wise fashion. Following thisaddition, the reaction mixture is raised to the boiling point andmaintained under reflux and anhydrous conditions for a period of 6hours. The reaction mixture is then filtered, concentrated, and theresidue chromatographed on florisil in the manner described in Example1, to provide the 3,3- ethylenedioxy- 1 7-vinylidene-5a -androstan- 160: -01 product. Part B 3,3-Ethylenedioxy-5a -pregnane-l6a ,17a ,2 ltn'ol-20-one To a solution of 500 mg. of 3,3-ethylenedioxy-17-vinylidene-51-androstan-161-o] in ml. of ether is added 1.0 g. of osmiumtetroxide and 1 m1. of 3 percent aqueous hydrogen peroxide. The reactionmixture is allowed to stand at room temperature for 10 days and is thenfiltered. The ethereal filtrate is washed with sodium thiosulfatesolution and water, dried over sodium sulfate and evaporated. Theresidue is purified on chromatographic magnesium silicate eluting withhexane and than with hexane: ethyl acetate (4:1) to yield 3,3-ethylenedioxy-Su -pregnanel 61 1 7a ,2 l -triol-20-one.

Hydrolysis of the ketal with hydrogen chloride in acetone afiordsSa-pregnane-Ku,17,2l-triol-3,20- dione,

EXAMPLE 11 Part A Gx-Methyl-Qa -fluoro-l7-vinylidene-51-androstane- 3,8, 1 1 B-diol Fifty milliliters of diethylene glycol monoethyl ether ismade anhydrous and pretreated with zinc dust in'accordance with themethods set forth in Examples 1 to 4, above. To this anhydrous,pretreated diethyleneglycol monoethyl ether are added 2 g. of(u-methyl-Qw fluoro- 1 7a -ethynyl- 1 7B-acetoxy-5a -androstane-3[3, 1 lB-diol. To the resulting solution are added 50 g. of zinc dust in aportion-wise fashion and at room temperature while stirring. Followingthe addition of the zinc dust, 1 ml. of 36 percent hydrogen chloridesolution is added to the reaction mixture. The reaction mixture is thenheated at the boiling point for a period of three hours whilemaintaining the entire mixture under anhydrous conditions. Following thereflux period, the solution is filtered, concentrated, and the residuechromatographed to provide the 61-methyl-9afluorol 7-vinylidene-Sa-androstane-3l3,1 l B-diol product. Part B fu-Methyl-9a-f1uoro-5apregnane-3B,1 1B 1 7 ,2 l-tetraol-ZO-one A mixtureof 25 g. of &1-methyl-9a-fluoro-l7-vinylidene-Sa-androstane-3,8,l1B-diol and 1.5 l. of

diisopropyl ether is added to a mixture of 102 g. of osmium tetroxide,500 m1. of diisopropyl ether and ml. of water. The resulting mixture isstirred for 4 days at 40 C., cooled and filtered. The filtrate is washedwith aqueous sodium thiosulfate solution and water, dried over magnesiumsulfate and evaporated. The residue is chromatographed on magnesiumsilicate eluting with isooctane to yield 61 -methyl-9b -fluoro-51pregnane-3B,l 13,17 ,2l-tetraol-20-one.

EXAMPLE 12 Part A 6,8,l6a-Dimethyl-17-vinylidene-5a-androstan-3B-ol Onehundred milliliters of anhydrous diethylene glycol dimethyl ether whichhas been pretreated with zinc is prepared as described in the foregoingexamples, Part A. To this is added one gram of 6,B,l6a-dimethyl- 1 7-ethyny1-l7/3-propionyloxy-5u -androstan-3B-ol. To the resultantsolution are added 10 g. of zinc dust in a portion-wise fashion withstirring and at room temperature. Following the addition of the zincdust, the reaction mixture is heated to the boiling point and maintainedunder reflux conditions for a period of hours, During the first 8 hoursof the reflux period, measures are taken to maintain the reactionmixture anhydrous. Following the reflux period, the solution is filteredand the filtrate concentrated to provide a residue which ischromatographed on silica-gel to provide the 63,160:- dimethyll7-vinylidene-5'1 -androsta.n-3fl-ol product. Part B 6,8,16a-Dirnethyl-l7-(3'-chlorobenzoyloxy)-5a -pregnan-3B-ol-20-one and 6B, 1 6a-dimethyl-2l- (3 '-chlorobenzoyloxy)-5a -pregnane-3B, 1 7a-diol-2O one To asolution of 1 g. of 6B,l6a-dimethyl-l7-vinylidene-Sa -androstan-3B-oldispersed in ml. of chloroform are added 1.3 g. of 85 percentmchloroperbenzoic acid. The resultant reaction mixture is allowed tostand at room temperature for 24 hours. After this period it isextracted with sodium bicarbonate, dried over sodium sulfate andevaporated. The residue after evaporation is chromatographed on florisileluting with benzene: 2 percent ethyl acetate to provide the 68,161-dimethyll 7a-(3- chlorobenzoyloxy )-5a -pregnan-3B-ol-20-one and 6B, 16a-dimethyl-2 l-( 3 '-chlorobenzoyloxy )-5a pregnane-3B, 17a-diol-20-one.

EXAMPLE 13 In accordance with the methods of the foregoing Examples thefollowing l7-vinylidene derivatives are prepared from the corresponding17a -ethynyl- 17B- acyloxy steroids:

6 -methyl- 1 7-vinylideneandrost-4-en-3-one,

(:1 -methyl- 1 7-vinylidenestr-4-en-3-one,

6 -fiuorol 7-vinylideneandrost-4-en-3-one,

(u -fluorol 7-vinylidenestr-4-en-3-one,

6/3-fluorol 7-vinylidenestr-4-en3-one,

6a ,7a -difluoromethylene- 1 7-vinylideneandrost-4- en-3-one,

(u ,7a -difluoromethylenel 7-vinylidenestr-4-en-3- one,

6x ,7@ -methylenel 7-vinylideneandrost-4-en-3-one,

1a ,2a -difluoromethylenel 7-vinylidenestr-4-en-3- one,

6-methyl- 1 7-vinylideneandrosta4,6-dien-3-one,

6-chlorol 7-vinylidenestra-4,6-dien-3-one,

6-fluorol 7-vinylidenestra-4,6-dien-3-one, l 7-vinylidenandrostal,4,6-trien-3-one, 6-chloro- 1 7-vinylidenandrostl ,4,6-trien-3-one, 61-chlorol 7-vinylidenandrosta-l ,4-dien-3-one, l 7-vinylideneandrostal,4-dien-3-one, l 7-vinylidenandrost-4-ene, 6): -methyl- 17-vinylideneandrostane-3B, 1 6a-diol 6B, l6a-dimethyl-Qx -fluorol7-vinylideneandrostane-SB, l 7B-diol, 6x -methyl-l7-vinylideneandrostane-3B, l l B-diol l 7-vinylideneandrostane-3/3, l6ozdiol, 1a ,Zx -oxidol 7-vinylideneandrostan-3B-ol,l7-vinylideneandrostane-3B, l lB-diol, 6a-flu0rol7-vinylideneandrostan-3B-ol, 9x l l ,B-oxidol7-vinylideneandrostan-3B-ol, 1 G1 l 6,8-difluorol7-vinylideneandrostan-3B-ol, 6,8-fluorol7-vinylideneandrostane-3/3,5a-diol, l ,B,2a-methylene- 17-vinylideneandrostan-3B-ol, 5 ,6-oxidol 7-vinylideneandrostan-3B-ol, l61 -triflu0romethyll 7-vinylideneandrostan-3B-ol, l7-vinylideneandrostane-3B, l lB-diol, 3,8-acetoxy-4B-methyl-l7-vinylidene androstane, l7 -vinylideneandrostan-3B-ol,and Q -fluorol7-vinylideneandrostane-3B, 1 lB-diol EXAMPLE 14 In accordance with themethods hereof and particularly by means of the methods of the processdescribed in Parts B of the appropriate foregoing examples, the abovelisted (Example 13) compounds can be converted to the corresponding 17a-hydroxy(acyloxy)-20- keto and 17a ,2 l-dihydroxy(acyloxy)-20-ketocompounds, to wit (u -methylpregn-4-ene-1 7a ,2 l-diol-3 ,20 -dione,

(a -methyl- 1 9-norpregn-4-ene- 1 704,2 l-diol-3,20

dione,

Gr -fluoropregn-4-ene- 1 711,2 1-diol-3 ,20 -dione,

61 -fluorol 9-norpregn-4-enel 7a,2 l-diol-3 ,20-

dione,

6,8-fluorol 9-norpregn-4-enel 7a,2 l -diol-3 ,20

dione, and so forth,

61 -methyl-2 l-acetoxypregn-4-en- 1 7a -ol-3 ,20-dione,

61 -methyl-2 l -acetoxy- 19-norpregn-4-en-l 7a -ol- 3,20 -dione,

6n -fluoro-2 l -acetoxypregn-4-en- 1 7a -0l-3 ,20 -dione,

dione,

6/3-fluoro-2 l-acetoxyl 9-norpregn-4-en- 1 701-01- 3,20-dione, and soforth,

(u -methyl- 1 7a-( 3 '-chlorobenzoyloxy)spregn-4-ene- 3,20-dione,

fix -methyl- 1 7a-( 3 '-chlorobenzoyloxy)- l 9-norpregn-4-ene-3,20-dione,

3,20-dione,

6a-fluoro- 1 7a-( 3 '-chlorobenzoyloxy 1 9-norpregn- 4-ene-3,20-dione,

6B-fluoro- 1 7a-( 3 '-chlorobenzoyloxy)- l 9-norpregn- 4-ene-3,20-dione,and so forth,

6a -methyl-2 l 3 -chlorobenzoyloxy)-pregn-4-en- 17a -ol-3,20-dione,

6 -methyl-2 1-( 3 '-chlorobenzoyloxy)- 1 9-norpregn- 4-en- 17a -o13,20-dione,

1 7a-ol-3,20-dione,

(u -fluoro-2 1-( 3 '-chlorobenzoyloxy l 9-norpregn-4- en- 1 7a-ol-3,20-dione,

1 9 6B-fluoro-2 l 3 -chlorobenzoyloxy l 9-norpregn-4- en- 1 7a-ol-3,20-dione, and so forth, 6a -methylpregnane-3B, lfu 1 7 ,2l-tetraol-20-one, 631th -dimethyl-91 -fluoropregnane-3B,l 1B, 1 7a ,21-

tetraol-ZO-one, 6a -methylpregnane-3B,l 1B, 1 7a, 2 l -tetraol-20-one,pregnane-Zifi, 16 17 ,21-tetraol-20-one,

1a ,2 -oxidopregnane-3B, l 701 ,2 l-triol-20-one, and

so forth,

313,2 1 -diacetoxy-61 methylpregnanel 6 1 7a -diol- 20-one,

318,2 1 -diacetoxy-6/3, 16x -dimethyl-Sbr fluoropregnane- 1 1,8, l7a-diol-20-one,

3B ,2 l -diacetoxy*-G -methylpregnane- 1 13, 17a -diol- 20-one,

3B, 1 6a ,2 l-triacetoxypregnan- 1 7 -ol-20-one,

a ,2a oxide-313,2 l-diacetoxypregnan-l 7oz-0l-20- one, and so forth,

6 -methyl- 1 7 3 '-chlorobenzoyloxy )pregnane- 3B, 161 -diol-20-one,

63,161 -dimethyl-Qx -fluoro- 2 7a 3'- chlorobenzoyloxy) pregnane 3B, 1lfi-diol-20-one,

6a -methyl- 1 7a 3 '-chlorobenzoyloxy )pregnane- 3B, 1 1 B-diol-ZO-one,

1 7a 3 '-chlorobenzoyloxy)pregnane-3,6, l 6a-diol- 20-one,

1a ,2a 1 7a 3 '-chlorobenzoyloxy )pregnan-SB -ol-20-one, and so forth,

6a-methyl-2 1 3 '-chlorobenzoyloxy)pregnane- 3,6, 161 l 7-triol-20-one,

6B, 1 61 -dimethyl-% -fluoro-2 l 3'-chlorobenzoyloxy )pregnane3B,l 1B, 17a-triol-20-one,

(n -methyl-2 1 3 -chlorobenzoyloxy)pregnane- 33,1 1,8,] 7-triol-20-one,

2 1-( 3 -chlorobenzoyloxy )pregnane-3B, 160:, l 70:

triol-20-one,

la ,2a-oxido-2 1 3 '-chlorobenzoyloxy )pregnane- 3B, 1 7a-diol-20-one,and so forth.

EXAMPLE 15 a-phthaloyloxy-a-pregnan-20-one, and 3fi-acetoxy- 2 l-phthaloyloxy-5a -pregnan-1 7a-ol-20-one.

EXAMPLE 16 A solution of g. of 17-vinylideneandrost-4-en-3- one in 125ml. of dioxane is treated with 10 ml. of ethyl orthoformate and 1 g. ofptoluenesulfonic acid, and the reaction mixture is allowed to stand atroom temperature for 6 hours. A few drops of pyridine are then added andthe solvent is evaporated to dryness under reduced pressure. The solidresidue is recrystallized from methylene chloridemethanol to yield3-ethoxyl 7-vinylideneandrosta-3,S-diene.

A mixture of 5 g. of 3-ethoxy- 1 7-vinylideneandrosta- 3,5-diene, 2g. ofanhydrous sodium acetate and 100 ml. of acetone is treated with 32 ml.of water. The solution is cooled to 5 C. and 1.1 molar equivalents of N-chlorosuccinirnide and 2 ml. of glacial acetic acid are added. Themixture is stirred for 30 minutes at the same temperature and thendiluted with water. After being allowed to stand at 0 C. for hours, thesolid is collected by filtration, washed with water and dried undervacuum to yield 6fi-chloro17-vinylideneandrost-4en-3-one which isrecrystallized from acetone. The corresponding 6or-chloro compound isobtained by dissolving this compound in glacial acetic acid andintroducing a slow stream of anhydrous hydrogen chloride over a periodof four hours and a temperature of 15 C. The solid which forms uponpouring this mix- 5 ture into water is collected by filtration, washedwith water and dried to yield fix-chlorwU-vinylideneandrost-4-en-3-onewhich is recrystallized from acetonezhexane.

A mixture of 6 g. of Gfl-chloro-l7-vinylideneandrost- 4-en-3-one, 100ml. of dioxane, 7 ml. of ethyl orthoformate and 0.7 g. ofp-toluenesulfonic acid is allowed to stand at room temperature for 1 5ehours, it is then neutralized with pyridine and evaporated to drynessunder reduced pressure. The residue is purified by chromatography onalumina, to give the pure 3-ethoxy- 6-chloro- 1 7-vinylideneandrost-3,S-diene.

A solution of 5 g. of3-ethoxy-6-chloro-l7-vinylidene-androsta-3-,5-diene in 20 ml. of dioxaneis cooled to 10 C. and treated with a mixture of 5.8 g. of2,3-dichloro-5,6-dicyano-l,4-benzoquinone, ml. of dioxane, 4 drops ofwater and 0.3 g. of p-toluenesulfonic acid, and the reaction mixture isstirred'at 10 C. for 2 hours. It is then filtered through 250 g. ofwashed alumina, eluting the product with methylene chloride, thusafiording 6-chloro-l7-vinylideneandrosta-4,6- dien-3-one, which isfurther purified by recrystallization from methylene chloride-methanol.

To a solution of L95 g. of 6-chloro-17-vinylideneandrosta-4,6-dien-3-onein ml. of dioxane is added 3.1 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and

' the mixture is refluxed under stirring for 20 hours. It is thencooled, the 2,3-dichloro-5,6-dicyano-l ,4- benzohydroquinone isseparated by filtration and the filtrate evaporated to dryness underreduced pressure. The residue is purified by thin layer chromatography,to provide 6chloro-l7-vinylideneandrosta- 1 ,4,6-trien- 3-one.

EXAMPLE 17 A solution of l g. of 3B-acetoxy-l7-vinylidenestr-4- ene inml. of methanol is treated with 500 mg. of potassium hydroxide in 1 ml.of water and the mixture is refluxed for 1 hour. The reaction mixture isthen poured into water and the solid which forms is collected byfiltration, washed with water to neutrality and air dried.Crystallization from acetone-ether afforded the pure SB-hydroxyl7-vinylidenestr-4-ene.

In a similar fashion, 3B-hydroxy-l7-vinylidenestra- 4,6-diene,3B-hydroxy-l7-vinylideneandrosta-4,6- diene and3B-hydroxy-6a-methyl-l7-vinylideneandrost-4-ene are obtained from thecorresponding 33- acetoxy compounds.

EXAMPLE 18 A mixture of 250 mg. of 3B-hydroxy-l7-vinylidenestr-4-ene, 1ml. of pyridine, and 1 ml. of

propionic anhydride is allowed to stand at room temperature for 24hours. The mixture is then poured into ice-water and the solid whichforms is collected by filtration, washed with water and dried to yield33- propionoxy-17-vinylidenestr-4-ene which is further purified throughrecrystallization from acetone-hexane.

In a similar manner but using other carboxylic acid anhydrides in placeof propionic anhydride v.g. caproic, valeric, enanthic andcyclopentylpropionic anhydride as esterifying agents the corresponding33- acyloxy-l7-vinylidenestr-4-ene compounds are obtained.

EXAMPLE 19 To a solution of l g. of 3B-hydroxy-l7-vinylidenestr- 4-enein 25 ml. of benzene is added 2 ml. of dihydropyran and approximatelyml. are distilled off to remove moisture. The mixture is then cooled toroom temperature, 0.1 g. of p-toluenesulfonic acid is added and theresulting reaction mixture is held at room temperature for 24 hours.Following this reaction period the reaction mixture is washed with 5percent aqueous sodium carbonate solution and water until neutral, driedover sodium sulfate and evaporated to dryness. The residue is purifiedby chromatography on alumina eluting the column with hexane, to furnish3,8- tetrahydropyran-Z '-yloxyl 7-vinylidenestr-4-ene, which isrecrystallized from pentane.

In a similar manner 3,8-hydroxy-l7-vinylidenestra- 4,6-diene, 3,B-hydroxy- 1 7-vinylideneandrosta-4,6- diene and3B-hydroxy-6z-methyl-l7-vinylideneandrost-4-ene are converted into thecorresponding tetrahydropyran-Z '-yl ethers.

EXAMPLE To a solution of 5 g. of3-ethoxy-17-vinylideneandrosta-3,5-diene (obtained as described inExample 16) in 100 ml. of acetone is added a solution of 2 g. of sodiumacetate in 32 ml. of water, and the resulting mixture is cooled to 05 C.Then, 1.1 molar equivalents of N-bromosuccinimide and 2 ml. of glacialacetic acid are added, and the reaction mixture is stirred for minutesat 0-5 C. At the end of this period the mixture is diluted with icewater and extracted with methylene chloride, the organic extracts arewashed with water to neutral dried over sodium sulfate and evaporated todryness under vacuo. Crystallization of the residue from acetone-etheraffords the pure 6,B bromol 7-vinylideneandrost-4-en-3-one.

- EXAMPLE 21 A solution of 6 g. of l7a-acetoxy-5a-pregnan-3Bol- 20-onein 120 ml. of pyridine is added to a mixture of 6 g. of chromic trioxidein 20 ml. of pyridine. The reaction mixture is allowed to stand at roomtemperature for 15 hours, diluted with ethyl acetate and filteredthrough Celite diatomaceous earth. The filtrate is washed well withwater, dried and evaporated to dryness to yield 17a -acetoxy-5-pregnane-3,20-dione which may be further purified by recrystallizationfrom acetonezhexane.

Two equivalents of bromine in 15 ml. of glacial acetic acid are addeddropwise to a solution of 1 g. of 17a -acetoxy-5a-pregnane-3,20-dione in25 ml. of

acetic acid containing a few drops of 4N hydrogen bromide in aceticacid. After being allowed to stand for five hours at room temperature,the mixture is poured into ice water and the solid which forms iscollected by filtration, washed well with water and dried. This materialis then refluxed for 14 hours with 2 g. of sodium iodide in 40 ml. ofZ-butanone, allowed to stand at room temperature for 12 hours, dilutedwith water, and extracted with ether. These extracts are washed withsodium thiosulfate solution and water and evaporated under reducedpressure. The residue is dissolved in 35 ml. of acetone, and treatedunder carbon dioxide with an aqueous solution of l l g. of chromicchloride. After allowing the mixture to stand at room temperature for 20minutes, water is added and the mixture is extracted with ether. Theseextracts are washed with water to neutrality, dried and evaporated. Theresidue is mixed with 0.8g. of potassium carbonate in 35 ml. of methanoland 7 ml. of water and refluxed for 30 minutes. The mixture is extractedwith chloroform and these extracts are chromatographed on alumina with7:3 chloroformzbenzene to yield 17oz -acetoxypregn-4- ene-3,20-dionewhich is recrystallized from ether:hexane.

In the manner corresponding with that described above in this example,the other corresponding 3- hydroxy-S compounds prepared as describedabove can be converted to the corresponding 3-keto-A" compounds. Inthose instances in which the compound also contains a hydroxyl groupwhich competes with the oxidation step (Paragraph 1 above) it ispreferable to first protect these groupings such as by forming the16,17- isopropylidenedioxy grouping in accordance with standardprocedures or by standard etherification or esterification at C- l 6 andC-2 1. These procedures can be illustrated as follows.

To 120 ml. of acetone containing 1 g. of 5apregnane-3,B,lfirx,17a,21-tetraol-20-one are added 30 drops of percent perchloric acid. Themixture is allowed to stand 1 hour at room temperature, 30 drops ofpyridine are added and the solution is evaporated to dryness underreduced pressure. Thirty milliliters of water are added to the residueand this mixture is extracted several times with ethyl acetate. Thecombined extracts are washed to neutrality with water, dried over sodiumsulfate and evaporated to dryness. The residue upon trituration withmethanol yields 1611,1701- isopropylidenedioxy-Sa pregnan-3B,21-diol-20-one.

The latter prepared compound when treated in accordance with ParagraphNo. 2 of the example is converted to 16 ,170:-isopropylidenedioxypregn-4-en-2lol-3,20-dione.

EXAMPLE 22 One gram of 2l-acetoxypregn-5-ene-1l,B,l7a-diol- 3,20-dioneis dissolved with slow heating in 12.5 ml. of dimethylformamide. To thecooled mixture is then added 0.42 g. of methanesulfonyl chloride and 0.5ml. of pyridine. After heating the reaction mixture at C. for 30 minutesit is cooled, diluted with water and extracted with ethyl acetate. Theextracts are washed with water, dried over sodium sulfate and evaporatedto yield 2l-acetoxypregna-4,9(ll)-dien-l7 -ol-3,20- dione which may befurther purified by recrystallization from acetone: hexane.

To a solution of L6 g. of 2 l-acetoxypregna-4,9( 1 1 dien- 1 7a-ol-3,20-dione in 4 ml. of chloroform is added over a 5 minute periodwith continuous stirring, a solution of 0.3 g. of chlorine in 10 ml. ofcarbon tetrachloride. After being allowed to stand at room temperaturefor 20 minutes, the mixture is treated with 10 ml. of 5 percent aqueoussodium carbonate solution and extracted with chloroform. The chloroformextracts are washed with water to neutrality, dried over sodium sulfateand evaporated to dryness to yield 9a 1 1 B-dichloro-Z l-acetoxypregn-4-en-1 7a -ol-3,20- dione which may be recrystallized fromacetone:hexane.

EXAMPLE 23 To a suspension of 1 g. of 16 -methyl-2l-acetoxypregn-4-ene-l15,17 1 -diol-3,20-dione in 7.5 ml. of anhydrous, peroxide-free dioxaneare added 1.2 ml. of freshly distilled ethyl orthoformate and 0.8 g. ofptoluenesulfonic acid. The mixture is stirred at room temperature for 15minutes and allowed to stand at room temperature for 30 minutes. Thereis then added 0.8 ml. of pyridine, followed by water untilsolidification occurs. This solid is collected by filtration, washedwith water and air dried to yield 3-ethoxy-lfu-methyl- 2l-acetoxypregna-3 ,S-diene-l 113, 17a -diol-20-one which isrecrystallized from acetonezhexane.

A mixture of 5 g. of3-ethoxylfix-methyl-Zl-acetoxypregna-3,5-diene-11B,l7a-diol-20-one, 2 g.of anhydrous sodium acetate and 100 ml. of acetone is treated with 32ml. of water. The solution is cooled to 5 C. and l. 1 molar equivalentsof N-chlorosuccinimide and 2 ml. of glacial'acetic acid are added. Themixture is stirred for 30 minutes at the same temperature and thendiluted with water. After being allowed to stand at 0 C. for 15 hours,the solid is collected by filtration, washed with water and dried undervacuum to yield 65- chlorol 61 -methyl-2 1 -acetoxypregn-4-enel l B, 17a diol-3,20-dione which is recrystallized from acetone. Thecorresponding 6a chloro compound is obtained by dissolving this compoundin glacial acetic acid and introducting a slow stream of anhydroushydrogen chloride over a period of 4 hours and a temperature of 15 C.The solid which forms upon pouring this mixture into water is collectedby filtration, washed with water and dried to yield61-chloro-l61-methyl-2l-acetoxypregn-4-ene-l 1B, 1 7a -diol-3,20-dionewhich is recrystallized from acetonezhexane.

EXAMPLE 24 A mixture of 0.5 g. of 91,]lB-dichloro-Zl-acetoxypregn-4-en-17a -ol-3,20-dione, 10 ml. of dioxaneand 0.35 of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is refluxed for 10hours. The mixture is then cooled, filtered and evaporated to dryness.The residue is dissolved in acetone and this solution is then filteredthrough 10 g. of alumina and concentrated to yield 901 1 l B-dichloro-2l-acetoxypregna-1,4-dien- 1 7a -ol- 3,20-dione which is further purifiedby recrystallization from acetone:hexane.

A mixture of l g. ofQ1,llB-dichloro-2l-acetoxypregn-4-en-l7a-ol-3,20-dione, 2 g. ofchloranil, ml. of ethyl acetate and 5 ml. of acetic acid is refluxedunder nitrogen for 96 hours. The mixture is then cooled and washed withcold 10 percent aqueous sodium hydroxide until the washings wascolorless. The organic solution is dried over sodium sulfate and theethyl acetate removed by evaporation. Upon chromatography of the residueon neutral alumina there is ob tained 9x ,1 1B-dichloro-Zl-acetoxypregna-4,6-dien-l 7 a-ol-3,20-dione which may befurther purified by recrystallization from acetonezhexane.

What is claimed is:

1. The process of preparing a compound of the formula wherein A is theremainder of the steroid molecule comprising the A, B, and C rings, R ishydrogen, hydroxy or acyloxy, and R is hydrogen or acyl which comprisesthe steps of a. treating a l7a-ethynyl-l7B-acyloxy steroid of theestrane or androstane series with zinc in an ethylene glycol ether toyield the corresponding l7-vinylidene steroid and b. oxidizing theresulting 17-vinylidene steroid with an agent selected from the groupconsisting of osmium tetroxide, either alone or in combination withhydrogen peroxide; a percarboxylic acid, phenyliodoso acetate, andmorpholine. 2. The process according to claim 1 wherein in step a) theethylene glycol ether is a monoor dilower alkyl ether of the diethyleneglycol and triethylene glycol series and step b) is conducted withosmium tetroxide or a percarboxylic acid.

3. The process according to claim 1 wherein step (a) is conducted withzinc dust in diethylene glycol dimethyl ether at a temperature rangingfrom C. to the boiling point of the reaction mixture and step (b) isconducted with osmium tetroxide or a percarboxylic acid at a temperaturebetween 0 C. and the boiling point of the reaction mixture.

4. The process according to claim 1 wherein step (a) is conducted underanhydrous conditions employing anhydrous diethylene glycol dimethylether and zinc dust at a temperature of from 140 C. to the boiling pointof the reaction mixture and step (b) is conducted at about roomtemperature under an inert gas atmosphere with osmium tetroxide in aninert organic ether solvent or with a percarboxylic acid in an inerthydrocarbon or halogenated hydrocarbon solvent.

5. The process according to claim 1 wherein in step (b) osmium tetroxideis employed to prepare the corresponding 17a ,2l-dihydroxy-20-ketopregnane.

6. The process according to claim 1 wherein in step (b) a percarboxylicacid is employed to prepare the corresponding 17a-acyloxy-20-ketopregnane and 17- hydroxy-2 l-acyloxy-ZO-ketopregnane.

7. The process which comprises the step of treating a17a-ethynyl-l7B-acyloxy steroid of the estrane or androstane series withzinc in an ethylene glycol ether to yield the correspondingl7-vinylidene steroid.

8. The process according to claim 7 wherein the ethylene glycol ether isa monoor dilower alkyl ether of the diethylene glycol and triethyleneglycol series.

9. The process according to claim 7 conducted with zinc dust indiethylene glycol dimethyl ether at a temperature ranging from 140 C. tothe boiling point of the reaction mixture.

10. A compound selected from the group of compounds represented by theformula:

4% CH; 1 /VW z R" wherein,

R is hydrogen, chloro, bromo, fluoro or methyl; R is hydrogen or methyl;R is x0 or the group R 2 in which R is hydrogen,

hydroxy or a conventional hydrolyzable ester or ether thereof;

each Z and Z is a carbon-carbon single bond, a carbon-carbon doublebond, or the group CXYin which each X and Y is hydrogen, fluoro, orchloro; provided that when R is hydrogen, Z is a. carbon-car- 16. Thecompound according to claim 11, a-fluorol7-vinylideneandrost-4-en-3-one.

17. The compound according to claim 1 l, GB-chlorol7-vinylideneandrost-4-en-3-one.

18. The compound according to claim 1, 6-chlorol7-vinylideneandrosta-4,6-dien-3-one.

19. The compound according to claim 1, 6-chlorol 7-vinylideneandrostal,4,6-trien-3-one.

20. The compound according to claim 11, 61,701- difluoromethylene- 17-vinylideneandrost-4-en-3-one.

21. The compound according to claim 11, 111,20!-difluoromethylene-17-vinylideneandrost-4-en-3-one.

22. The compound according to claim 12, l7-vinyi fllg nip d according toclaim 12, l7-vinylidenestra-4,6-dien-3-one.

24. The compound according to claim 12, 6amethyl- 17-vinylidenestr-4-en-3-one.

25. The compound according to claim 13, 3B- hydroxy-l7-vinylidenestr-4-ene and its acetate.

2. The process according to claim 1 wherein in step a) the ethyleneglycol ether is a mono- or dilower alkyl ether of the diethylene glycoland triethylene glycol series and step b) is conducted with osmiumtetroxide or a percarboxylic acid.
 3. The process according to claim 1wherein step (a) is conducted with zinc dust in diethylene glycoldimethyl ether at a temperature ranging from 140* C. to the boilingpoint of the reaction mixture and step (b) is conducted with osmiumtetroxide or a percarboxylic acid at a temperature between 0* C. and theboiling point of the reaction mixture.
 4. The process according to claim1 wherein step (a) is conducted under anhydrous conditions employinganhydrous diethylene glycol dimethyl ether and zinc dust at atemperature of from 140* C. to the boiling point of the reaction mixtureand step (b) is conducted at about room temperature under an inert gasatmosphere with osmium tetroxide in an inert orgaNic ether solvent orwith a percarboxylic acid in an inert hydrocarbon or halogenatedhydrocarbon solvent.
 5. The process according to claim 1 wherein in step(b) osmium tetroxide is employed to prepare the corresponding 17 Alpha,21-dihydroxy-20-ketopregnane.
 6. The process according to claim 1wherein in step (b) a percarboxylic acid is employed to prepare thecorresponding 17 Alpha -acyloxy-20-ketopregnane and 17 Alpha-hydroxy-21-acyloxy-20-ketopregnane.
 7. The process which comprises thestep of treating a 17 Alpha -ethynyl-17 Beta -acyloxy steroid of theestrane or androstane series with zinc in an ethylene glycol ether toyield the corresponding 17-vinylidene steroid.
 8. The process accordingto claim 7 wherein the ethylene glycol ether is a mono- or dilower alkylether of the diethylene glycol and triethylene glycol series.
 9. Theprocess according to claim 7 conducted with zinc dust in diethyleneglycol dimethyl ether at a temperature ranging from 140* C. to theboiling point of the reaction mixture.
 10. A compound selected from thegroup of compounds represented by the formula:
 11. The compoundaccording to claim 10 wherein R6 is methyl and R7 is oxo.
 12. Thecompound according to claim 10 wherein R6 is hydrogen and R7 is oxo. 13.The compound according to claim 10 wherein R7 is the grouping in whichR9 is hydrogen, hydroxy or a conventional hydrolyzable ester or etherthereof.
 14. The compound according to claim 11 which is17-vinylideneandrost-4-en-3-one.
 15. The compound according to claim 11,6 Alpha -methyl-17-vinylideneandrost-4-en-3-one.
 16. The compoundaccording to claim 11, 6 Alpha -fluoro-17-vinylideneandrost-4-en-3-one.17. The compound according to claim 11, 6 Beta-chloro-17-vinylideneandrost-4-en-3-one.
 18. The compound according toclaim 1, 6-chloro-17-vinylideneandrosta-4,6-dien-3-one.
 19. The compoundaccording to claim 1, 6-chloro-17-vinylideneandrosta-1,4,6-trien-3-one.20. The compound according to claim 11, 6 Alpha ,7 Alpha-difluoromethylene-17-vinylideneandrost-4-en-3-one.
 21. The compoundaccording to claim 11, 1 Alpha ,2 Alpha-difluoromethylene-17-vinylideneandrost-4-en-3-one.
 22. The compoundaccording to claim 12, 17-vinylidenestr-4-en-3-one.
 23. The compoundaccording to claim 12, 17-vinylidenestra-4,6-dien-3-one.
 24. Thecompound according to claim 12, 6 Alpha-methyl-17-vinylidenestr-4-en-3-one.
 25. The compound according to claim13, 3 Beta -hydroxy-17-vinylidenestr-4-ene and its acetate.